This invention relates to a new, alternate process for preparing methylvanillyl ketone (MVK), or 4-hydroxy-3-methoxyphenylacetone, which is a useful intermediate for the synthesis of methyldopa, one of the most important antihypertensive agents.
The use of MVK in the methyldopa process has been disclosed in U.S. Pat. No. 2,868,818 which comprises the addition of a cyanide anion to MVK to form 4-methyl-4-(4-hydroxy-3-methoxybenzyl)hydantoin followed by basic hydrolysis to form .alpha.-methyl-.beta.-(4-hydroxy-3-methoxyphenyl)alanine. Subsequent acidic hydrolysis produces methyldopa, i.e., .alpha.-methyl-.beta.-(3,4-dihydroxyphenyl)alanine.
Presently, MVK is manufactured from vanillin and nitroethane [Kulka et al, J. Am. Chem. Soc., 65, 1184 (1943)]. However, this process suffers from the high cost of vanillin and the fact that there is only one supplier for nitroethane.
For these reasons, an alternate process for the production of MVK is desirable to safeguard the continuous production of methyldopa.
The novel process of the present invention concerns the direct oxidation of unprotected isoeugenol to form a glycol intermediate followed by subsequent acidic conversion to MVK. Although the process includes two chemical reactions, it is virtually a single-step "through process". MVK is the first and only isolated product.
The peroxide-oxidation of a protected isoeugenol, i.e., acetyl isoeugenol, to form an epoxide precursor of MVK is known (K. Freudenberg et al, Chem. Ber., 76, pp. 1005-1006, 1943). However, Freudenberg et al's process is not a "through process". It involves three steps, all of which require the isolation of products. It also suffers from low yield (30%).
Moreover, the novel process of this invention is distinguishable from Freudenberg et al's process. First, as will be shown later in Equation A, the present process oxidizes unprotected isoeugenol to generate a glycol intermediate instead of an epoxide. Second, the glycol intermediate generated does not come from the hydrolysis of a preceding epoxide. The epoxide simply does not exist due to the presence of a free phenol group in isoeugenol.
Therefore, it is an object of the present invention to provide a new, alternate process for the production of methylvanillyl ketone from isoeugenol.
It is also an object of this invention to provide a process which is economically more advantageous than the current vanillin process for the manufacturing of MVK.
Still another object of this invention is to provide a "through process" for preparing MVK which requires no isolation of products before that of MVK and thus is simpler, shorter, and more efficient than Freudenberg et al's synthesis.